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      O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

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          Abstract

          Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. YAP has been reported to play a pivotal role in controlling ferroptotic death, and the expression of YAP is enhanced and stabilized by O-GlcNAcylation. However, whether O-GlcNAcylation can increase the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis remains unknown. In the present study, we found that O-GlcNAcylation increased the sensitivity of HCC cells to ferroptosis via YAP. Moreover, YAP increased the iron concentration in HCC cells through transcriptional elevation of TFRC via its O-GlcNAcylation. With YAP knockdown or YAP-T241 mutation, the increased sensitivity to ferroptosis induced by O-GlcNAcylation was abolished. In addition, the xenograft assay confirmed that O-GlcNAcylation increased ferroptosis sensitivity via TFRC in vivo. In summary, we are the first to find that O-GlcNAcylation can increase ferroptosis sensitivity in HCC cells via YAP/TFRC. Our work will provide a new basis for clinical therapeutic strategies for HCC patients.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Regulation of ferroptotic cancer cell death by GPX4.

            Wan Seok Yang, Rohitha SriRamaratnam, Matthew E Welsch … (2014)
            Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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              ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

              Sebastian Doll, Bettina Proneth, Yulia Tyurina … (2017)
              Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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                Author and article information

                Contributors
                Lei Jin: jin_yeye@163.com
                Qiuhui Pan: panqiuhui_med@163.com
                Journal
                Journal ID (nlm-ta): Cell Death Discov
                Journal ID (iso-abbrev): Cell Death Discov
                Title: Cell Death Discovery
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2058-7716
                Publication date (Electronic): 16 April 2021
                Publication date PMC-release: 16 April 2021
                Publication date Collection: 2021
                Volume: 7
                Electronic Location Identifier: 83
                Affiliations
                [1 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, Department of Clinical Laboratory Medicine, Shanghai Children’s Medical Center, School of Medicine, , Shanghai Jiaotong University, ; 200127 Shanghai, China
                [2 ]GRID grid.412538.9, ISNI 0000 0004 0527 0050, Department of Clinical Laboratory, , Shanghai Tenth People’s Hospital of Tongji University, ; 200072 Shanghai, China
                [3 ]GRID grid.24516.34, ISNI 0000000123704535, Department of Clinical Laboratory, , Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, ; 200434 Shanghai, China
                [4 ]GRID grid.507037.6, Faculty of Medical Laboratory, , Shanghai University of Medicine and Health Sciences, ; 201318 Shanghai, China
                Article
                Publisher ID: 468
                DOI: 10.1038/s41420-021-00468-2
                PMC ID: 8052337
                PubMed ID: 33863873
                SO-VID: 5e0b8039-0457-4dcb-bfee-7991b790de68
                Copyright © © The Author(s) 2021
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 26 January 2021
                Date revision received : 14 March 2021
                Date accepted : 25 March 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81871727
                Award ID: 81930066
                Award Recipient :
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                Keywords: cell death,cancer
                Data availability:
                Keywords: cell death, cancer

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